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Mai Motomontant Diu to Di Un an Online MAIMOTOMONTANT US009944986B2 DIU TO DI UN ANONLINE (12 ) United States Patent (10 ) Patent No. : US 9 , 944 , 986 B2 Nagy (45 ) Date of Patent: Apr . 17 , 2018 ( 54 ) THERAPEUTIC TARGETS FOR Hirschhorn et al. (Genetics in Medicine. vol. 4 , No. 2 , pp . 45- 61 , ALZHEIMER ' S DISEASE Mar . 2002 ) . * Lucentini et al ( The Scientist ( 2004 ) vol. 18 , p . 20 ) . * ( 71 ) Applicant : The University of Birmingham , Langdahl ( Journal of Bone and Mineral Research 2000 vol . 15 , No. 3 , pp . 402 -414 ) .* Birmingham (GB ) Wall (Nature Reviews Genetics ( 2003) vol. 4 , pp . 587 -597 ) . * (72 ) Inventor : Zsuzsanna Nagy , Birmingham (GB ) Abramsson et al. , “ No Association of LOXLI Gene ( 73 ) Assignee : The University of Birmingham , Polymprophisms with Alzheimer ' s Disease ” , Neuromol. Med . , 13 : 160 - 166 ( 2011 ) . Birmingham , West Midlands (GB ) Bonda et al. , “ Novel therapeutics for Alzheimer' s disease : An ( * ) Notice : Subject to any disclaimer , the term of this update ” , Curr. Opin . Drug Discov . Devel ., 13 ( 2 ) : 235 - 246 ( 2010 ) . patent is extended or adjusted under 35 Bove et al. , “ Fighting neurodegeneration with rapamycin : mecha nistic insights ” , Nature Reviews, Neuroscience , 12 : 437 -452 (2011 ) . U . S . C . 154 (b ) by 101 days . Caccamo et al. , “ Molecular Interplay between Mammalian Target of ( 21 ) Appl . No . : 14 /413 , 659 Rapamycin (mTOR ) , Amyloid - B , and Tau ” , J . Biol. Chem . , 285 ( 17 ) : 13107 - 13120 ( 2010 ) . (22 ) PCT Filed : Jul. 11 , 2013 Cai et al. , “ Mammalian Target of Rapamycin : A Valid Therapeutic Target Through the Autophagy Pathway for Alzheimer ' s Disease ? ” , ( 86 ) PCT No .: PCT/ GB2013 / 051843 Journal of Neuroscience Research , 90 : 1105 - 1118 (2012 ) . Cascalheira et al . , " Serum homocysteine : Interplay with other $ 371 ( c )( 1 ) , circulating and genetic factors in association to Alzheimer ' s type ( 2 ) Date : Jan . 8 , 2015 dementia ” , Clinical Biochemistry , 42 : 783 - 790 (2009 ) . Clifford et al ., “ Large - scale analysis of non - synonymous coding ( 87 ) PCT Pub . No. : WO2014 / 009733 region single nucleotide polymorphisms” , Bioinformatics, 20 ( 7 ) : 1006 - 1014 ( 2004 ) . PCT Pub . Date : Jan . 16 , 2014 Erikkson et al ., “ Associations of gene sequence variation and serum levels of C - reactive protein and Interleukin - 6 with Alzheimer ' s (65 ) Prior Publication Data disease and dementia ” , J . Alzheimers Dis . , 23 ( 2 ) : 361 - 369 ( 2011 ) . Finckh , “ The Future of genetic association studies in Alzheimer US 2015 /0141491 A1 May 21 , 2015 disease ” , J . Neural. Transm , 110 : 253 - 266 ( 2003 ) . Forlenza et al ., “ Diagnosis and biomarkers of predementia in Foreign Application Priority Data Alzheimer ' s disease ” , BMC Medicine , 8 : 89 (2010 ) . ( 30 ) Gustaw - Rothenberg et al ., “ Biomarkers in Alzheimer ' s disease : 1212334 . 5 past , present and future ” , Biomark . Med ., 4 ( 1 ) : 15 - 26 (2010 ) . Jul . 11 , 2012 (GB ) .. Heinonen et al. , “ Deciphering downstream gene targets of P13K / mTOR /p70S6K pathway in breast cancer” , BMC Genomics, 9 : 348 (51 ) Int. Ci. ( 2008 ) . C12Q 1 /68 ( 2006 . 01 ) Hong et al. , “ Genome- Wide and Gene- Based Association Impli C12N 15 / 113 ( 2010 . 01) cates FRMD6 in Alzheimer Disease ” , Human Mutation , 33 ( 3 ) : ( 2006 .01 ) 521 - 529 (2012 ) . A61K 31 /436 Flex et al ., “ Polymorphisms of the Macrophage Inhibitory Factor GOIN 33 / 50 ( 2006 .01 ) and C -Reactive Protein Genes in Subjects with Alzheimers Demen (52 ) U . S . CI. tia ” , Dement . Geriatr. Cogn . Disord ., 18 : 261 -264 ( 2004 . CPC .. .. C12Q 1 /6883 (2013 . 01 ) ; A61K 31/ 436 Kok et al. , “ CRP gene variation affects early development of ( 2013 .01 ) ; C12N 15 / 113 ( 2013 .01 ) ; GOIN Alzheimer ' s disease -related plaques” , Journal of Neuroinflamma tion , 8 : 96 (2011 ) . 33 /5023 (2013 .01 ) ; C12N 2310 / 14 (2013 .01 ) ; Kramer et al. , “ Alzheimer disease pathology in cognitively healthy C120 2600 / 106 ( 2013 .01 ) ; C12Q 2600 / 118 elderly : A genome- wide study” , Neurobiology of Aging , 32 : 2113 ( 2013. 01 ) ; C12Q 2600/ 136 (2013 . 01 ) ; C12Q 2122 ( 2011 ) . 2600 / 156 (2013 .01 ) ; C12Q 2600 / 158 Lesseux et al ., “ Syk -dependent mTOR activation in follicular (2013 .01 ) lymphoma cells ” , Blood , 108 ( 13 ) : 4156 -4162 ( 2006 ) . Li et al. , “ Levels of mTOR and its downstream targets 4E - BP1, (58 ) Field of Classification Search eEF2 , and eEF2 kinase in relationships with tau in Alzheimer ' s None disease brain ” , FEBS Journal , 272 : 4211 -4220 (2005 ) . See application file for complete search history . Liu et al. , “ A Genomewide Screen for Late -Onset Alzheimer Disease in a Genetically Isolated Dutch Population ” , The American ( 56 ) References Cited Journal of Human Genetics , 81: 17 -31 ( 2007) . U . S . PATENT DOCUMENTS (Continued ) Primary Examiner — Katherine D Salmon 2002/ 0015941 Al * 2 / 2002 Kim . .. .. .. .. GOIN 33 /5008 (74 ) Attorney , Agent, or Firm — Kathleen D . Rigaut; 435 / 4 2003 /0092019 A1 * 5 / 2003 Meyer . .. .. .. .. .. .. .. CO7K 14 / 47 Dann , Dorfman , Herrell and Skillman , P . C . 435 / 6 . 14 (57 ) ABSTRACT The present invention relates to novel methods for the FOREIGN PATENT DOCUMENTS prevention , treatment and diagnosis of Alzheimer ' s disease . In addition , the invention relates to methods for assessing an WO 2011/ 012672 A1 2 /2011 individual' s susceptibility or pre - disposition to Alzheimer ' s disease . The methods of the present invention involve the use of therapeutic targets and diagnostic and /or predictive OTHER PUBLICATIONS markers within the mTOR signalling pathway . The methods Morita ( AJH 2006 vol. 19 pp . 593 -600 ) . * also involve screening subjects for genetic polymorphisms Bertram ( The American Journal of Human Genetics Nov . 7 , 2008 associated with rapamycin - sensitive genes . vol. 83 pp . 623 -632 ). * 4 Claims, 34 Drawing Sheets US 9 ,944 , 986 B2 Page 2 References Cited Ueberham et al. , “ Altered subcellular location of phosphorylated ( 56 ) SMads in Alzheimer' s disease” , European Journal of Neuroscience , 24 : 2327 - 2334 (2006 ) . OTHER PUBLICATIONS Oijen et al . , “ Polymorphisms and haplotypes in the C - reactive McKhann et al. , “ Clinical diagnosis of Alzheimer' s disease : Report protein gene and risk of dementia ” , Neurobiology of Aging , 28 : 1361- 1366 ( 2007 ) . of the NINCDS- ADRDA Work Group * under the auspices of Xiao et al. , “ Lysyl Oxidase , Extracellular Matrix Remodeling and Department ofHealth and Human Services Task Force on Alzheim Cancer Metastasis ” , Cancer Microenvironment, 5 : 261 - 273 (2012 ) . er' s Disease ” , Neurology , 34 : 939 - 944 ( 1984 ) . Yates et al. , “ Dysfunction of the mTOR pathway is a risk factor for Mendelsohn et al. , “ Rapamycin As an Antiaging Therapeutic ? : Alzheimer ' s disease ” , Acta Neuropathologica Communications, 1 : Targeting Mammalian Target of Rapamycin to Treat Hutchinson 3 ( 2013 ) . Gilford Progereia and Neurodegenerative Diseases” , Rejuvenation Yates et al. , “ Role of the Proliferation -Related Molecules in the Research , 14 ( 4 ) : 437 -441 (2011 ) . Pathogenesis of Alzheimer ' s Disease ” , A Thesis submitted to the Morita et al . , “ Association Study Between C - Reactive Protein University of Birmingham for the degree of Master of Philosophy , Genes and Ischemic Stroke in Japanese Subjects ” , AJH , 19 : 593 pp . 1 -332 , Apr. 2012 . 600 (2006 ) . Zemke et al ., “ The mTOR Pathway as a Potential Target for the Morita et al. , “ Polymorphism of the C -Reactive Protein (CRP ) Gene Development of Therapies Against Neurological Disease ” , Drug is Related to Serum CRP Level and Arterial Pulse Wave Velocity in News Perspect , 20 ( 8 ) : 495 -499 (2007 ) . Healthy Elderly Japanese ” , Hypertens. Res. , 29 : 323 -331 (2006 ) . Genolet et al ., “ An approach to analyse the specific impact of Nagy, “ The dysregulation of the cell cycle and the diagnosis of rapamycin on mRNA -ribosome association ” , BMC Medical Alzheimer ' s disease” , Biochimica et Biophysica Acta , 1772 : 402 Genomics, 1 : 33 ( 2008 ) . 408 ( 2007 ) . Search Report, dated Aug. 1 , 2016 , issued in corresponding Euro Oddo , “ The role of mTOR signaling in Alzheimer ' s disease” , pean Patent Application No. 13 740 046 . 1 . Frontiers in Bioscience, S4 : 941 - 952 (2012 ) . International Search Report /Written Opinion , dated Jan . 15 , 2014 , Perry et al. , " A New Alzheimer ' s Disease Interventive Strategy : issued in corresponding PCT/GB2013 / 051843 . GLP - 1 ” , Current Drug Targets , 5 : 565 -571 (2004 ) . Biesecker , Leslie G . et al ., “ The ClinSeq Project : Piloting large Perry et al ., “ Enhancing Central Nervous System Endogenous scale genome sequencing for research in genomic medicine ” , GLP - 1 Receptor Pathways for Intervention in Alzheimer' s Dis Genome Research , 19 ( 9 ) : 1665 - 1674 ( 2009 ) . ease ” , Current Alzheimer Research , 2 : 377 - 385 (2005 ) . Connelly , Jessica J . et al. , “ Genetic and functional association of Santos et al. , “ Effects of rapamycin and TOR on aging and memory : FAM5C with myocardial infarction ” , BMC Medical Genetics , 9 : 33 implications for Alzheimer ' s disease” , Journal of Neurochemistry , ( 2008 ) . 117 : 927 -936 ( 2011) . European Examination Report , dated May 3 , 2017 , issued in cor Sun et al ., " Protective Effects of Bone Morphogenetic Protein 7 responding European Patent Application No . 13740046 . 1 . Against Amyloid - Beta Induced Neurotoxicity in PC12 Cells ” , Neu roscience , 184 : 151 - 163 (2011 ) . * cited
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